Systemic therapies for salivary gland carcinomas: an overview of published clinical trials

Background: There is no consensus about effective systemic therapy for salivary gland carcinomas (sgcs). Our aim was summarized the clinical trials assessing the systemic therapies (ST) on sgcs.Material and Methods: Electronic searches were carried out through MEDLINE/pubmed, EMBASE, Scopus, Web of Science, and the Cochrane Library databases, and gray literature. Results: Seventeen different drugs were evaluated, and the most frequent histological subtype was adenoid cysticcarcinoma (n=195, 45.5%). Stable disease, observed in 11 ST, achieved the highest rate in adenoid cystic carcinoma treated with sunitinib. The highest complete (11.1%) and partial response (30.5%) rates were seen in androgen receptor-positive tumors treated with leuprorelin acetate. Conclusions: Despite all the advances in this field, there is yet no effective evidence-based regimen of ST, with all the clinical trials identified showing low rates of complete and partial responses. Further, translational studies are urgently required to characterize molecular targets and effective ST. (AU)

Cell block preparation as an adjunctive tool after fine-needle aspiration cytology for screening oral and maxillofacial diseases.

OBJECTIVE: To describe the use of cell block (CB) preparation from fine-needle aspiration cytology for diagnosing oral and maxillofacial diseases. STUDY DESIGN: We performed a retrospective analysis of 568 samples collected by our laboratory for CB preparation from fine-needle aspiration cytology of the oral and maxillofacial region between January 2001 and October 2021. We performed cytologic diagnoses and compared them with the available histopathologic diagnoses to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CB preparation for identifying malignant lesions. RESULTS: The most frequent diagnosis was pleomorphic adenoma (n = 44, 7.7%), followed by metastatic squamous-cell carcinoma (n = 28, 4.9%) and odontogenic keratocyst (n = 26, 4.6%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CB preparation, which revealed detailed morphologic and architectural patterns, were 70.0%, 100.0%, 100.0%, 62.5%, and 80.0%, respectively. CONCLUSIONS: Cell block preparation from fine-needle aspiration cytology of the oral and maxillofacial region may be a useful adjunctive diagnostic tool for diagnosing oral and maxillofacial diseases because it reveals morphologic and architectural patterns similar to those shown on histopathologic slides, leading to the better categorization of diseases.

The importance of early treatment of oral squamous cell carcinoma: Case report.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is frequently diagnosed at an advanced stage, with the five-year survival rate varying around 50%, however, ifs the sooner OSCC in early-stage is treated, the lower the chances of recurrence and death. In this study, we described an OSCC diagnosed early, highlighting how the early surgical excision prevents the morbidity. CASE REPORT: A 74-year-old man presented a whitish and symptomatic plaque and a discreet ulcerated area on the right lateral border of the tongue. Due to close contact with the second inferior molar, a clinical diagnosis of a frictional keratosis was suspected, however as the lesion persisted after two weeks of follow-up, an incisional biopsy was performed and the microscopic features revealed an OSCC. Early surgical resection was performed, preventing the morbidity and improve benefits to patient. CONCLUSION: OSCC can manifest of several clinical forms, including indolent appearances, which can delay the diagnosis, and consequently the prognosis. Further, it is important to recognize and not neglect any intraoral lesions, in order to avoid the far more invasive surgery that a more advance disease would imply.

Hybrid Neurofibroma/Schwannoma of the Oral Cavity: A Rare Case Report and Literature Review.

Hybrid peripheral nerve sheath tumors show combined features of more than one type of conventional benign peripheral nerve sheath tumors. There are few cases reported of hybrid peripheral nerve sheath tumors in the head and neck region. A 68-year-old female patient was referred for evaluation of an oral swelling lasting five years. Intraoral examination revealed a small mobile nodule located in the lower vestibule. The patient underwent excisional biopsy and microscopic evaluation showed typical features of neurofibroma enclosing areas with palisading nuclei compatible with Antoni A pattern, which are seen in schwannomas. These regions showed strong and diffuse immunoreactivity for S100 protein and moderate positivity in the neurofibroma area. CD34 was positive in the neurofibroma area and entrapped axons were positive for neurofilament. The final diagnosis was oral hybrid neurofibroma-schwannoma tumor. Hybrid peripheral nerve sheath tumors, although extremely rare, may arise within the oral cavity. To the best of our knowledge, this is the first neurofibroma-schwannoma tumor reported in the oral cavity. Recognizing hybrid peripheral nerve sheath tumors as a distinct clinicopathological entity is important because they may also be associated with syndromic disorders.

Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFκB and histone deacetylation inhibition.

Despite many progresses in the development of new systemic therapies for oral squamous cell carcinoma (OSCC), the five-year survival rate of OSCC is low. The traditional chemotherapies approach (cisplatin - CDDP) shows some limitations like drug toxicity, limited efficacy, and drug resistance. Promising studies suggested OSCC cancer stem cells (CSC) presented resistance to CDDP. We have previously studied many targets, and we extensively showed the efficacy of the NFκB signaling and the role of histones acetylation, on different malignant tumors, including adenoid cystic carcinoma and mucoepidermoid carcinoma, but until then the effects of the NFkB inhibitor and histone deacetylase (HDAC) inhibitor on the biology of OSCC were not evaluated. Here we assessed the pharmacological inhibitor of NFκB emetine and HDAC inhibitor SAHA on the behavior of CSC derived from OSCC. Our data suggested that CDDP administration resulted in reduced viability of bulk OSCC cells and increased CSC. A single and isolated shot of emetine and SAHA were able to disrupt CSC by inhibiting the NFκB pathway and increasing the histone acetylation levels, respectively. Further, the combined administration of emetine and SAHA presented the same CSC disruption as seen in emetine alone.

Oral lymphangioma-like Kaposi sarcoma: a Brazilian case report in a scenario of a still high number of HIV infections.

We present a challenging case of HIV-related lymphangioma-like Kaposi sarcoma (LLKS) affecting the oral cavity. A 54-year-old Brazilian male patient was referred to our center complaining of bleeding lesions affecting the oral cavity for 2 months. Interestingly, these oral lesions were the first clinical manifestation of HIV infection. Clinically, multiple erythematous nodular and patch lesions were observed. An incisional biopsy was performed, revealing numerous microscopic angled and irregular vascular channels lined with flattened endothelial cells. More cellularized and solid areas consisting of more fusiform cells with little pleomorphism and with slit-like vascular channels were noted. Based on immunoreactivity for CD31, CD34, D2-40, and HHV-8, the final diagnosis was oral LLKS. Highly active antiretroviral therapy (HAART) was initiated with dolutegravir, tenofovir, and lamivudine. During follow-up, the patient showed KS metastases to other sites and a chemotherapeutic protocol was initiated. Regression of the oral lesion was clearly noted by the clinicians 1 year after the KS diagnosis. Dentists should be able to recognize systemic diseases that affect the oral cavity such as KS in order to make an early diagnosis of its oral manifestations and to implement effective therapeutic measures to ensure a better prognosis.

Fully digital pathology laboratory routine and remote reporting of oral and maxillofacial diagnosis during the COVID-19 pandemic: a validation study.

The role of digital pathology in remote reporting has seen an increase during the COVID-19 pandemic. Recently, recommendations had been made regarding the urgent need of reorganizing head and neck cancer diagnostic services to provide a safe work environment for the staff. A total of 162 glass slides from 109 patients over a period of 5 weeks were included in this validation and were assessed by all pathologists in both analyses (digital and conventional) to allow intraobserver comparison. The intraobserver agreement between the digital method (DM) and conventional method (CM) was considered almost perfect (κ ranged from 0.85 to 0.98, with 95% CI, ranging from 0.81 to 1). The most significant and frequent disagreements within trainees encompassed epithelial dysplasia grading and differentiation among severe dysplasia (carcinoma in situ) and oral squamous cell carcinoma. The most frequent pitfall from DM was lag in screen mirroring. The lack of details of inflammatory cells and the need for a higher magnification to assess dysplasia were pointed in one case each. The COVID-19 crisis has accelerated and consolidated the use of online meeting tools, which would be a valuable resource even in the post-pandemic scenario. Adaptation in laboratory workflow, the advent of digital pathology and remote reporting can mitigate the impact of similar future disruptions to the oral and maxillofacial pathology laboratory workflow avoiding delays in diagnosis and report, to facilitate timely management of head and neck cancer patients. Graphical abstract.

Oral focal mucinosis: A multi-institutional study and literature review.

BACKGROUND: Oral focal mucinosis (OFM) is a rare benign condition of unknown etiology, considered the oral counterpart of cutaneous focal mucinosis. We report the clinicopathologic features of 21 cases of OFM in conjunction with a review of the literature. METHODS: Clinical data were collected from the records of five oral and maxillofacial pathology services. All cases were evaluated by hematoxylin and eosin staining, histochemistry, and immunohistochemistry (vimentin, S-100, α-SMA, CD34, and mast cell). RESULTS: The series comprised 14 females (66.7%) and seven males (33.3%), with a mean age of 48.2 ± 20.7 years (range: 8-77 years) and a 2:1 female-to-male ratio. Most of the lesions affected the gingiva (n = 6, 28.6%) and presented clinically as asymptomatic sessile or pedunculated nodules with fibrous or hyperplasic appearance. All cases were negative for S-100 protein, CD34, and α-SMA and positive for Alcian blue staining. Conservative surgical excision was the treatment in all cases, and there was only one recurrence. CONCLUSION: OFM is a rare benign disorder that is often clinically misdiagnosed as reactive lesions or benign proliferative processes. Dermatologists and pathologists should consider OFM in the differential diagnosis of soft tissue lesions in the oral cavity, mainly located in the gingiva.

Metastatic Neuroblastoma to the Mandible of Children: Report of Two Cases and Critical Review of the Literature.

Neuroblastoma is the most common extracranial solid cancer of infancy, occurring mainly in the adrenal gland, with high metastatic potential. However, involvement of the head and neck region is rare. Here, we present two cases of metastatic neuroblastoma of childhood, in which a mandibular swelling was the first sign of disseminated disease. Case 1 describes a 4-year-old boy with a 2-week history of painful swelling in the left mandibular region, body soreness and weakness. Panoramic radiography and computed tomography showed a destructive lesion in the left mandibular ramus. Case 2 describes a 3-year-old boy with a 1-month history of swelling in the right mandibular area. Panoramic radiograph and cone-beam computed tomography showed a destructive lesion in the right body and ramus of the mandible, displacing tooth germs, with the destruction of vestibular and lingual bone cortices. In both cases, microscopic analyses revealed a diffuse proliferation of small, round, and blue cells with hyperchromatic nuclei and scant cytoplasm. While Case 1 was more undifferentiated, Case 2 presented eosinophilic areas suggestive of neuropil. A large immunohistochemical panel was performed, showing expression of neural markers such as CD56, neuron-specific enolase (in Case 2), chromogranin, and synaptophysin. Both lesions presented a high proliferation index (Ki67 > 70% and 80%, respectively). Positron emission tomography-computed tomography revealed ipsilateral adrenal primary lesions in both cases, with multiple bone metastatic lesions. Besides the mandible, multiple sites of the axial and appendicular skeleton were affected. Treatment consisted of induction chemotherapy, adrenalectomy, consolidation chemoradiotherapy, and post-consolidation therapy.

Central odontogenic fibroma: an international multicentric study of 62 cases.

OBJECTIVE: The aim of this study was to report the clinicopathologic features of 62 cases of central odontogenic fibroma (COdF). STUDY DESIGN: Clinical and radiographic data were collected from the records of 13 oral pathology laboratories. All cases were microscopically reviewed, considering the current World Health Organization classification of tumors and were classified according to histopathologic features. RESULTS: There were 43 females and 19 males (average age 33.9 years; range 8-63 years). Clinically, COdF lesions appeared as asymptomatic swellings, occurring similarly in the maxilla (n = 33) and the mandible (n = 29); 9 cases exhibited palatal depression. Imaging revealed well-defined, interradicular unilocular (n = 27), and multilocular (n = 12) radiolucencies, with displacement of contiguous teeth (55%) and root resorption (46.4%). Microscopically, classic features of epithelial-rich (n = 33), amyloid (n = 10), associated giant cell lesion (n = 7), ossifying (n = 6), epithelial-poor (n = 3), and granular cell (n = 3) variants were seen. Langerhans cells were highlighted by CD1a staining in 17 cases. Most patients underwent conservative surgical treatments, with 1 patient experiencing recurrence. CONCLUSIONS: To the best of our knowledge, this study represents the largest clinicopathologic study of COdF. Most cases appeared as locally aggressive lesions located in tooth-bearing areas in middle-aged women. Inactive-appearing odontogenic epithelium is usually observed within a fibrous/fibromyxoid stroma, occasionally exhibiting amyloid deposits, multinucleated giant cells, or granular cells.

Immunoexpression of BDNF, TrkB, and p75NTR receptors in peripheral neural lesions of the head and neck.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) and neurotrophin receptors have been recognized as fundamental regulators of normal brain development, homeostasis, and plasticity. They have also been studied in the behavior of central nervous system tumors. Here, we studied the pattern of BDNF, TrkB and p75NTR immunoexpression in peripheral benign and malignant neural lesions in head and neck. METHODS: This cross-sectional analytical study included 79 cases of head and neck neural lesions. Nineteen cases of traumatic neuromas (TN), 20 cases of granular cell tumors (GCT), 16 cases of neurofibromas (NF), 20 cases of schwannomas (SC), and 4 malignant peripheral nerve sheath tumor (MPNST) were submitted to immunohistochemistry with BDNF, TrkB, and p75NTR antibodies. A semi-quantitative analysis was performed. RESULTS: The analysis of BDNF demonstrated a high percentage of positive cells in TN, GCT and SC with a decrease in cases of NF and MPNST. TrkB presented a lower significant immunoexpression in GCT in relation to the TN, NF, SC, and MPNST (P < .0001); and TN showed less percentage of positive cell compared to SC (P = .0017). Regarding p75NTR, the percentage of positive cell was significantly reduced in MPNST compared GCT (P = .009), NF (P = .0138) and SC (P = .0069). Also, a decrease in TN compared to GCT (P = .007) was observed. CONCLUSIONS: Our results showed the immunoreactivity of BDNF, TrkB, and p75NTR in head and neck peripheral neural lesions. Reduction of BDNF and p75NTR in MPNST might suggest down-regulation during the acquisition of malignant phenotype.

Retrospective application of the Milan System for reporting salivary gland cytopathology: A Cancer Center experience.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was recently proposed. Herein, we retrospectively applied this nomenclature system to salivary gland lesions sampled by ultrasound-guided fine-needle aspiration (FNA). METHODS: All cases of salivary gland FNA with available surgical follow-up, in the period from 2014 to 2017 at our institution were reviewed and reclassified according to one of the six categories of the MSRSGC, blind to the surgical outcome. Overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, as well as risks of neoplasm (RON) and risk of malignancy (ROM) for each of the proposed categories. RESULTS: There were 104 salivary gland lesions, with a female predominance (57.7%), most cases from the parotid gland (89.4%). Mean age was 53.2 years. Distribution of the specimens according to the Milan System was as follows: 19.2% nondiagnostic (ND), 8.7% non-neoplastic (NN), 9.6% atypia of undetermined significance (AUS), 40.4% benign neoplasm (BN), 14.4% salivary gland neoplasm of uncertain malignant potential (SUMP), 1.9% suspicious for malignancy (SFM), and 5.8% malignant. Sensitivity, specificity, PPV, and NPV using MSRSGC were calculated as 75%, 98.4%, 88.9%, and 95.3%, respectively. RON/ROM for each category were 60%/15% for ND, 44.4%/0% for NN, 90%/40% for AUS, 100%/9.5% for BN, 100%/13.3% for SUMP, 50%/50% for SFM and 100%/100% for malignant. CONCLUSION: The use of the Milan System proved to be a useful method to predict the risk of neoplasm and malignancy in the sample studied, with high sensitivity and specificity.

Increased Tumor Immune Microenvironment CD3+ and CD20+ Lymphocytes Predict a Better Prognosis in Oral Tongue Squamous Cell Carcinoma.

Background: Oral tongue squamous cell carcinoma (OTSCC) causes over 350,000 cases annually and particularly impacts populations in developing countries. Smoking and alcohol consumption are major risk factors. Determining the role of the tumor immune microenvironment (TIME) in OTSCC outcomes can elucidate immune mechanisms behind disease progression, and can potentially identify prognostic biomarkers. Methods: We performed a retrospective study of 48 OTSCC surgical specimens from patients with tobacco and alcohol exposures. A panel of immunoregulatory cell subpopulations including T (CD3, CD4, CD8) and B (CD20) lymphocytes, dendritic cells (CD1a, CD83), macrophages (CD68), and immune checkpoint molecules programmed cell death protein 1 (PD-1) and ligand 1 (PD-L1) were analyzed using immunohistochemistry. The levels of immune effector cell subpopulations and markers were analyzed in relation to overall survival. Results: Pathological characteristics of the tumor microenvironment included inflammatory infiltrates (83.3%), desmoplasia (41.6%), and perineural invasion (50.0%). The TIME contained high levels of T cells (CD3+, CD4+, and CD8+) and B cells (CD20+), as well as immature (CD1a) and mature (CD83) dendritic cells, PD-1, and PD-L1. Higher numbers of TIME infiltrating CD3+ T cells and CD20+ B cells were predictive of better survival, while higher levels of CD83+ mature dendritic cells predicted better survival. CD3+ T cells were identified as an independent prognostic marker for OTSCC. Lastly, CD3+ T cells were strongly correlated with the number of CD8+ cells and PD-L1 expression. Conclusion: Our findings provide evidence that the TIME profile of OTSSC impacted prognosis. The high expression of CD3+ T cells and B cells are predictive of better overall survival and indicative of an immunologically active, inflammatory TIME in patients with better survival. The number of CD3+ T cells was an independent prognostic marker.